Pharmaceutical composition based on valproic acid and a process for preparing it

ABSTRACT

New pharmaceutical composition based on valproic acid and one of the pharmaceutically acceptable salts thereof, obtained by a new galenic preparation process which makes it possible to improve and simplify the galenic production, this composition also containing excipients which favorably modify its kinetics and its bioavailability.

This application is a divisional of Ser. No. 07/313,304, filed Jan. 21,1989, now U.S. Pat. No. 5,017,613 which is a continuation of Ser. No.07/004,303, filed Jan. 8, 1987, now abandoned, which is a continuationof Ser. No. 06/631,602, filed Jul. 17, 1984, now abandoned.

Dipropylacetic or valproic acid (D C I) of formula ##STR1## and sodiumvalproate are used in human therapy for their antiepileptic properties.Thus, sodium valproate is administered in different galenic forms suchas drinkable solutions or tablets. It is known that, after oraladministration, the bioavailability in the blood of valproic acid isnearly 100% and that the maximum concentration, which is rapidlyreached, may cause side effects.

Moreover, the production of the tablets mentioned above has a number ofdisadvantages which it is felt should be mentioned:

1. granulation can only be carried out in the presence of a binder andwith a wetting solvent;

2. before compression an adsorbent product and a lubricant must beadded;

3. the core thus produced can only be given a coating which dissolves inthe stomach if it has already been coated with an isolating lacquer;

4. the finished weight of the tablet is relatively great and theexcipients represent approximately 40% of the total weight of thetablet;

5. all these operations have to be carried out in a dehydratedatmosphere with a relative humidity of 30%.

The present invention relates to new pharmaceutical compositions whichcan be administered by oral route and which contain a mixture ofvalproic acid and one of the pharmaceutically acceptable salts thereof.

It relates more particularly to the preparation of tablets the finalweight of which is significantly less than that obtained by theconventional methods of galenic preparation.

The applicants have also discovered that the use, in the same tablet, ofvalproic acid combined with one of the pharmaceutically acceptable saltsthereof and of a delaying excipient has the unexpected advantage ofpreventing the maximum blood concentration of the active principle fromcausing side effects (resulting from the substantial increase in theconcentration of free valproic acid), whilst maintaining a bloodconcentration which is useful in terms of a delayed action; it also hasthe advantage of unexpectedly improving the process for producing thetablet and thus avoiding the various galenic disadvantages mentionedhereinbefore.

The invention thus relates to the production of pharmaceuticalspecialities which satisfy the above criteria.

In fact, pharmaceutical specialities are available on the market inFrance, containing either 200 mg or 500 mg of sodium valproate perdosage unit, the excipient used consisting of calcium silicateexcipient, polyvidone excipient, magnesium stearate, talc,polyoxyethylene glycol 400, corn starch, titanium oxide, yellow ironoxide, cellulose acetophthalate and diethylphthalate, the finishedweight being, for example, 800 mg in the case of the coated tabletcontaining 500 mg of sodium valproate, corresponding to 434 mg ofvalproic acid.

The processes for producing specialities based on valproic acid or oneof the pharmaceutically acceptable salts thereof all use the stage ofgranulation carried out with a binder such as polyvidone excipient and awetting solvent such as isopropyl alcohol or water. An absorbent productsuch as calcium silicate excipient and a lubricant such as magnesiumstearate are added to the resulting granules before compression; aftercompression, the core thus produced is given an isolating coatingconsisting of polyvidone or methacrylate and then, if desired, anenteric release coating. Thus, the core has a weight of 562.5 mg and theisolating layer and the coating have a weight of 237.5 mg, giving afinal weight of 800 mg.

It was thus thought necessary to improve the processes for preparingthese pharmaceutical specialities so as to obtain a finished weight forthe tablet of less than 800 mg, whilst retaining the same quantity ofactive principle expressed as valproic acid and the same characteristicsof bioavailability.

The invention thus relates to the production of a speciality which hasthe above characteristics but in which the methods of production aresimplified and improved.

Thus, the granules for compression are formed directly by simply mixingsuitable proportions of valproic acid and one of the pharmaceuticallyacceptable salts thereof in the absence of any binder or granulatingsolvent. In fact, valproic acid is added slowly, either directly or byspraying, to the valproic acid salt; the granular agglomeration occursautomatically in a few minutes and the granules thus obtained are passedthrough a screen for calibration. This operation may be carried out inan atmosphere of 55-60% relative humidity, without the risk of anyuptake of moisture.

The compressibility of these granules is very good and moreover thevalproic acid acts as a lubricant. To avoid any tendency to stick to thepunch, it was found necessary to add precipitated silica to the granulesbefore compression.

Another advantage of the invention is the possibility of directlyapplying any coating, including an enteric coating, to the core, thusdoing away with the nuisance and time spent on applying the isolatinglayer.

In other words, the advantages of the invention are

granulation by simply mixing valproic acid and one of thepharmaceutically acceptable salts thereof, without any solvent and hencewithout any drying

a simplified formula

a lower core weight

no need to work in a dehydrated atmosphere with a relative humidity of30%

a less hygroscopic core

a lower end weight for the tablet.

A process carried out at ambient temperature for producing the tabletsaccording to the invention is described in detail hereinafter, as anon-restrictive example; the proportions given relate to 1000 tablets:145 g of valproic acid, in liquid form, are added slowly or sprayed onto 333 g of sodium valproate, which is in powder form; after the rapidformation of a granular agglomeration, the granules are passed through ascreen in order to calibrate them.

52 g of precipitated silica are added to the granules before compressionand then the mixture is compressed The cores thus obtained each weigh530 mg, valproic acid constitutes 30.33% of the active principle andsodium valproate is 69.67% of the active principle; expressed asvalproic acid, each tablet contains 434 mg corresponding to 500 mg ofsodium valproate. These tablets are lacquered for example usinghydroxypropylmethyl cellulose (18 mg/tablet) and glycerol (7 mg/tablet)or any other suitable lacquer.

The production of these tablets according to the invention may be showndiagrammatically as follows, the quantities given corresponding to theproduction of 1000 tablets. ##STR2##

Various tests were carried out in which the proportions of valproic acidand sodium valproate were varied and suitable results were obtained withmixtures containing between 15 and 48% of valproic acid and between 85and 52% of sodium valproate. Similarly, the behaviour in moisture of themixture of sodium valproate and valproic acid showed that, after 14 daysof contact with 55% relative humidity, the mixture containing 10% ofvalproic acid and 90% of sodium valproate had taken up 22% of moisture,the mixture containing 20% of valproic acid and 80% of sodium valproatehad taken up 9% of moisture, whereas the mixture containing 30% ofvalproic acid and 70% of sodium valproate had taken up virtually nomoisture.

However, it should be pointed out that it is always possible to addvarious conventional excipients during production of the core, dependingon the equipment used and the operating conditions. These additives,which constitute a small percentage, will not modify the characteristicsof bioavailability of the medicament of the invention described above.

As has already been pointed out, tests on comparative bioavailabilitywere carried out with standard commercial tablets containing 500 mg ofsodium valproate and the tablets according to the invention which alsocontained 500 mg of sodium valproate (or 434 mg of valproic acid).

Six healthy volunteers aged 24 to 30 were each given a single dose oftwo tablets corresponding to 1000 mg of sodium valproate or 868 mg ofvalproic acid; the tablet was given with a glass of water after thevolunteers had fasted and the first meal, which was low in lipids, wasgiven about 4 hours after the tablets were taken The commercial productand the medicament of the invention were given successively with a restperiod of at least 8 days between two sequences.

Blood samples were taken at the following times: 0.10 min, 30 min, 45min, 1 h, 1 h 30, 2 h, 2 h 30, 3 h, 3 h 30, 4 h, 4 h 30, 5 h, 6 h and 8h, the time 0 corresponding to the first appearance of traces ofvalproic acid in the plasma.

The plasma was separated by centrifuging at 3000 rpm for a period of 5minutes and then frozen until required for analysis.

The valproic acid was titrated in the samples by gas-liquidchromatography using flame ionisation detection in a Hewlett - Packard5710 A apparatus fitted with an HP 7672 A automatic injector.

50 μg of sodium 1-methyl-cyclohexyl-carboxylate (internal standard) and0.100 ml of 0.5N hydrochloric acid were added to 0.5 ml of plasma. Thevalproic acid and the internal standard were extracted with 0.5 ml ofchloroform by vortex agitation for 1 minute and then centrifuging for 15minutes at 6000 rpm. A calibration range was prepared in exactly thesame way in the plasma.

The average plasma concentrations of valproic acid expressed as μg/ml asa function of time are shown in the following table:

    ______________________________________                                        Products                                                                             Standard commercial                                                                          Medicament according to the                             Time   medicament (batch A)                                                                         invention (batch B)                                     ______________________________________                                        0          ε      ε                                           10  mn     45             47                                                  30  mn     90             86                                                  45  mn     97             95                                                  1   h      89             86                                                  1   h 30   87             85                                                  2   h      85             82                                                  2   h 30   74             71                                                  3   h      70             68                                                  3   h 30   65             63                                                  4   h      62             60                                                  4   h 30   57             59                                                  5   h      55             54                                                  6   h      51             50                                                  8   h      45             46                                                  ______________________________________                                    

The results obtained indicate the following points:

1. the bioavailability of the commercial product and of the medicamentaccording to the invention are substantially the same;

2. the maximum concentration is, after a period of 45 minutes, 97 μg/mlfor a batch A and 95 μg/ml for batch B;

3. the areas under the curves are substantially identical for bothbatches:

940±75 for batch A

949±80 for batch B

These results confirm that the production of the tablets according tothe process of the invention does not alter the bioavailability of theactive principle as existed with the commercially available product.

As has been pointed out hereinbefore, the applicants have alsodiscovered that the use, in the same tablet, of valproic acid combinedwith one of the pharmaceutically acceptable salts thereof and of adelaying excipient has the unexpected advantage of preventing themaximum blood concentration of the active principle from causing sideeffects, whilst prolonging this blood concentration, within the scope ofa delayed action, within the range of therapeutic concentrations.

The granules for compression are formed directly by simple mixing ofsuitable proportions of valproic acid to which ethyl cellulose has beenadded and one of the pharmaceutically acceptable salts thereof which mayor may not contain eudragit, in the absence of any binder or anygranulating solvent. The mixture of valproic acid and ethyl cellulose isadded slowly to the mixture of valproic acid salt and eudragit; thegranular agglomeration is formed automatically in a few minutes and thegranules thus obtained are passed through a screen for calibration. Thisoperation may be carried out in an atmosphere of 55 to 60% relativehumidity without any danger of absorption of moisture.

In order to avoid any tendency to stick to the punch, it was foundnecessary to add precipitated silica to the granules before compression.

A process carried out at ambient temperature for producing the tabletsaccording to the invention is described in detail hereinafter, as anon-restrictive example; the proportions given refer to 1000 tablets:145 g of valproic acid together with 12 g of ethyl cellulose are addedslowly to the mixture consisting of 333 g of sodium valproate and 113 gof eudragit; after the rapid formation of a granular agglomeration, thegranules are passed through a screen for calibration. 52 g ofprecipitated silica are added to the granules before compression andthen the mixture is compressed. The cores thus obtained each weigh 655mg and are coated, for example, with 18 mg of hydroxypropymethylcellulose and 7 mg of glycerol or any other suitable lacquer; the tabletC is obtained which corresponds to 500 mg of sodium valproate (or 434 mgexpressed as valproic acid).

In another variant of the invention, no eudragit is added to the 333 gof sodium valproate. All the operations of production are carried out inthe same way, but the weight of each core is then 542 mg and the coatedtablet weighs 567 mg; a tablet B is obtained which corresponds to 500 mgof sodium valproate.

Other variants of the invention consist in modifying the respectivequantities of ethyl cellulose (from 5 to 125 mg per dosage unit) andeudragit (from 50 to 150 mg per dosage unit) depending on the desired"delaying effect" and dispensing with an enteric coating on the core.

The production of the tablets according to the invention may bediagrammatically shown as follows: ##STR3##

In order to demonstrate the delaying effect of the medicament accordingto the invention, dissolution tests were carried out in vitro andbioavailability tests were carried out in vivo, the control tablet Thaving been produced in the same way but containing no ethyl cellulosenor eudragit. The production of the tablet T can be diagrammaticallyshown as follows: ##STR4##

In Vitro Tests (Dissolution Test)

The dissolution test which was carried out was intended to determine thequantity of free valproic acid which went into solution in an artificialmedium with a phosphate buffer at pH 6.8, the quantity of activeprinciple being determined by titration in samples taken from thedissolution medium at various predetermined intervals of time.

The test was carried out using the technique described in Technical NoteNo. 79 (Pro-Pharmacopoea (Bull. Ordre Pharm, March 1980, no. 231).

The results obtained are shown in the following table. They areexpressed as percent based on the quantity of valproic acid (434 mg)contained in each dosage unit.

    ______________________________________                                               Products                                                               Time     Tablet T     Tablet C Tablet D                                       ______________________________________                                        0             0            0      0                                           30    mn      60          24     38                                           1     h       83          31     49                                           1     h 30    90          35     61                                           2     h       95          40     68                                           2     h 30    97          43     73                                           3     h      101          45     79                                           3     h 30   102          48     83                                           4     h      103          50     87                                           4     h 30   103          53     88                                           5     h      103          56     90                                           5     h 30   103          58     93                                           6     h      103          60     95                                           ______________________________________                                    

In Vivo Tests (Bioavailability)

The tests on comparative bioavailability were carried out with thetablets T, tablets C and tablets D, each of these tablets containing 500mg of sodium valproate.

Six healthy volunteers aged 24 to 30 were each given a single dose oftwo tablets corresponding to 1000 mg of sodium valproate or 868 mg ofvalproic acid; the tablets were accompanied by a glass of water afterthe volunteer had fasted and the first meal, which was low in lipids,was given about 4 hours after the tablet was taken. The tablets C, D andT were given successively with a rest period of at least eight daysbetween the two sequences.

The blood measurements were taken at the following times: 0.10 min, 30min, 45 min, 1 h, 1 h 30, 2 h, 2 h 30, 3 h, 3 h 30, 4 h, 4 h 30, 5 h, 6h and 8 h, the time 0 corresponding to the first appearance of traces ofvalproic acid in the plasma.

The method of extraction and blood titration of the valproic acid areidentical to those described above.

The average plasma concentrations of valproic acid expressed in μg/ml asa function of time are shown in the following table:

    ______________________________________                                               Products                                                               Time     Tablet T     Tablet C Tablet D                                       ______________________________________                                        0            ε    ε                                                                            ε                                    10    mn     47           15     22                                           30    mn     86           24     38                                           45    mn     95           29     44                                           1     h      86           35     49                                           1     h 30   85           46     57                                           2     h      82           55     69                                           2     h 30   71           58     70                                           3     h      68           60     70                                           3     h 30   63           63     69                                           4     h      60           65     67                                           4     h 30   59           67     65                                           5     h      54           69     65                                           6     h      50           73     63                                           8     h      46           65     59                                           ______________________________________                                    

The following findings are obtained from the in vitro and in vivoresults:

1. the dissolution tests are in favour of the delaying effect of thetablets C and D compared with the tablets T;

2. The bioavailability tests confirm the results obtained in vitro,namely that, compared with the tablets T, the tablets C and D have thecharacteristics of a delaying effect; in fact, the formulation of themedicament of the invention unexpectedly and favourably modifies thebioavailability of valproic acid (tablets C and D); this change in thebioavailability makes it possible to avoid the side effects caused bythe sudden introduction of valproic acid into the circulation (tabletT); the maximum concentration is obtained after 45 minutes at 95 μg/mlfor batch T, after 6 hours at 73 μg/ml for batch C and after 2 hours 30minutes to 3 hours at 70 μg/ml for batch D.

These results therefore confirm the delaying effect of the medicament ofthe invention which makes it possible to flatten the bioavailabilitycurve and hence to avoid the side effects of the sudden introduction ofvalproic acid into the circulation and also to avoid any majordifferences between the maximum and minimum concentrations which makethe level of valproicaemia at any time during repeated administrationvery haphazard.

Other tests have been carried out in man by oral administration of asingle dose of 1000 mg of sodium valproate either in the form of adrinkable solution, solution E, or in the form of tablets according tothe invention according to formula C with a delayed action Additionaltests were carried out on tablets of formula C by administering twotablets in a single dose per day for 8 days corresponding to a dailydose of 1000 mg of sodium valproate. The tests were carried out on 8healthy volunteers according to the plan described above (the curvesobtained are shown in the accompanying single drawing):

1) After Single Administration

The pharmacokinetic parameters determined were:

C max : maximum plasma concentration observed, expressed in μg/ml⁻¹.

T max : time taken to reach the C max, expressed in hours afteradministration of the product

AUC₀ : area under the curve of the plasma concentrations of valproicacid as a function of time, expressed in μg.h.ml⁻¹.

    ______________________________________                                                Parameter                                                             Form      C max        T max    AUC.sub.0.sup.∞                         ______________________________________                                        solution E                                                                              90.2 ± 3.3                                                                              0.4 ± 0.1                                                                           1330 ± 117                                 tablet C  50.5 ± 3.6                                                                              9.1 ± 0.8                                                                           1592 ± 129                                 ______________________________________                                    

A study of this table shows

a slowing down of the speed of availability of the valproic acid fromtablet C according to the invention.

A greater quantity of active principle which is bioavailable afteradministration of the medicament according to the invention, explainedby a reduced coating of enzymes.

2) After Administration for 8 Days:

The pharmacokinetic parameters determined were:

Values of the Cmin in the steady state were calculated from the valuesof the minimum plasma concentrations obtained before administration ondays J₁₉, J₂₀ and J₂₁ and 24 hours after the last administration on J₂₁.

For all the 8 volunteers studied, the average is 42.6±4.6 μg.ml⁻¹.

Speed of Passage

The average values of the parameters of the maximum plasma concentrationand Tmax obtained after the last administration were 77.2±5.8 μg.ml⁻¹and 6.9±0.9 h, respectively.

Area Under the Curve in the Interval τ Between Two Administrations

The values below show that on repeated administration and when a stateof equilibrium is attained, the intensity of passage of the activeprinciple is comparable to that which was calculated between the time 0and infinity during a single dosage: ##STR5##

Kinetics of Elimination

It was interesting to note that, when the repeated administration wasstopped, the kinetics of elimination of the medicament were hardlyaltered compared with that which followed the first administration.

    β=0.036±0.003 h.sup.-1 after the last dosage

    β=0.040±0.003 h.sup.-1 after the first dosage

3) On studying the results obtained, it was found that:

3.1. After oral administration of a single dose in man, the speed ofentry of the valproic acid into the general circulation from the tabletsaccording to the invention is significantly slower than a form withimmediate release (solution E).

With the same dosage of active principle, the quantity of valproic acidwhich is bioavailable is about 20% greater when the tablets according tothe invention are administered.

The kinetics described by the medicament of the invention correspond tothe objective sought: flattening of the plasma peak, bioavailabilitywhich is at least equal and possibly improved: these criteria correspondperfectly to the definition of a controlled release form.

3.2. A study of the bioavailability of the tablets according to theinvention was expanded to include tests on chronic administration. Adose equivalent to 1000 mg of sodium valproate was administered in asingle dosage per 24 hours until a state of equilibrium was obtained Thekinetics after the last dosage are linear under the experimentalconditions described.

The controlled release form makes it possible to prolong the period ofpresence in the plasma within the range of the effective concentrationswithout reaching the high concentrations which are responsible forintolerance Moreover, it makes it possible to reduce substantially thehabitually considerable differences between the maximum and minimumconcentrations which make the level of valproicaemia at any momentduring repeated administration very haphazard.

Thus, the tablets according to the invention satisfy the aims of theinvention and are favourable in terms of therapeutic use.

We claim:
 1. An orally administrable controlled release tabletpharmaceutical composition comprising a ratio of about one mole ofvalproic acid to about two moles of sodium valproate and a carrier forcontrolled release, wherein said tablet is produced without the additionof binder or granulating solvent.
 2. The pharmaceutical composition ofclaim 1 wherein the carrier is polymeric methacrylate.
 3. Thepharmaceutical composition of claim 1 wherein the carrier is ethylcellulose.
 4. The pharmaceutical composition of claim 1 wherein thecarrier comprises ethyl cellulose and polymeric methacrylate.
 5. Thepharmaceutical composition of claim 1 wherein the carrier comprisesethyl cellulose and polymeric methacrylate, further comprising ananti-sticking amount of precipitated silica.
 6. The pharmaceuticalcomposition of claim 5 coated with an enteric coating.